Wang et al (2018) Acute Hepatic Porphyrias: Review and Recent Progress (says some people with CFS have been misdiagnosed with this)

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https://aasldpubs.onlinelibrary.wiley.com/doi/full/10.1002/hep4.1297

Review
Open Access
Acute Hepatic Porphyrias: Review and Recent Progress
Bruce Wang
Sean Rudnick
Brent Cengia
Herbert L. Bonkovsky
First published: 20 December 2018
https://doi.org/10.1002/hep4.1297
Supported by National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases (U54 DK 083909) and by Protect the Future funding provided by the American Porphyria Foundation.


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Abstract
The acute hepatic porphyrias (AHPs) are a group of four inherited diseases of heme biosynthesis that present with episodic, acute neurovisceral symptoms. The four types are 5‐aminolevulinic acid (ALA) dehydratase deficiency porphyria, acute intermittent porphyria, hereditary coproporphyria, and variegate porphyria. Their diagnoses are often missed or delayed because the clinical symptoms mimic other more common disorders. Recent results indicate that acute intermittent porphyria, the most severe of the more common types of AHP, is more prevalent than previously thought, occurring in about 1 in 1600 Caucasians, but with low clinical penetrance (approximately 2%‐3%). Here we provide an updated review of relevant literature and discuss recent and emerging advances in treatment of these disorders. Symptomatic attacks occur primarily in females between 14 and 45 years of age. AHP is diagnosed by finding significantly elevated levels of porphyrin precursors ALA and porphobilinogen in urine. Acute attacks should be treated promptly with intravenous heme therapy to avoid the development of potentially irreversible neurologic sequelae. All patients should be counseled about avoiding potential triggers for acute attacks and monitored regularly for the development of long‐term complications. Their first‐degree relatives should undergo targeted gene testing. Patients who suffer recurrent acute attacks can be particularly challenging to manage. Approximately 20% of patients with recurrent symptoms develop chronic and ongoing pain and other symptoms. We discuss newer treatment options in development, including small interfering RNA, to down‐regulate ALA synthase‐1 and/or wild‐type messenger RNA of defective genes delivered selectively to hepatocytes for these patients. We expect that the newer treatments will diminish and perhaps obviate the need for liver transplantation as treatment of these inborn metabolic disorders.

Abbreviations

• AHPs

• acute hepatic porphyrias

• AIP

• acute intermittent porphyria

• ALA

• aminolevulinic acid

• ALADP

• ALA dehydratase deficient porphyria

• ALAS

• ALA synthase

• CEP

• congenital erythropoietic porphyria

• ED

• emergency department

• EPP

• erythropoietic protoporphyria

• HCC

• hepatocellular carcinoma

• HCP

• hereditary coproporphyria

• HEP

• hepatoerythropoietic porphyria

• HMBS

• hydroxymethylbilane synthase

• mRNA

• messenger RNA

• PBG

• porphobilinogen

• PCT

• porphyria cutanea tarda

• PPOX

• protoporphyrinogen oxidase

• siRNA

• small inhibitory RNA

• VP

• variegate porphyria

• XLP

Contrary to urban legend, it is not difficult to establish or rule out a diagnosis of AHP, provided that physicians or other providers think of the diagnosis and perform the appropriate diagnostic testing. As in the described clinical vignette, AHP should be considered in any patient, but especially in women in their child‐bearing years who present with recurrent, severe episodes of abdominal pain. The pain may occur elsewhere as well, including the back, extremities or chest, but is first and foremost in the abdomen. The first test of choice for diagnosis is a single random urine screening for ALA, PBG, and creatinine—not porphyrins. In our experience, the most frequent errors lie in (1) not considering the diagnosis in a timely fashion, leading to the average 15‐year delay in the United States from time of first symptoms to eventual correct diagnosis,7 and (2) ordering a random urine screening for porphyrins rather than for ALA and PBG. As described subsequently (in the “Secondary Porphyrinurias” section), many patients without any form of porphyria will show mild to moderate increases in urinary porphyrins, especially in coproporphyrins I and III. When these are found in patients with diverse symptoms, including abdominal pain, joint pain, muscle pain, fibromyalgia, anxiety and chronic fatigue syndrome, such patients, unfortunately, are labeled as having porphyria when they do not. Too often, this leads to the patients and their physicians ascribing a plethora of symptoms to an inaccurate diagnosis. Unfortunately, some of these patients have had central venous ports inserted and have been treated with recurrent infusions of intravenous heme, sometimes with disastrous results, such as recurrent infections and/or thrombosis of ports and central veins, thrombophlebitis, sepsis, and development of secondary iron overload (heme is 9% iron by weight).